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Validation of Genetic Case-Control Studies in AIDS and Application to the CX3CR1 Polymorphism

Hendel, Houria; Winkler, Cheryl; An, Ping; Roemer-Binns, Elisabeth; Nelson, George; Haumont, Philippe; O'Brien, Steve; Khalilli, Kamel; Zagury, Daniel; Rappaport, Jay; Zagury, Jean-François
JAIDS Journal of Acquired Immune Deficiency Syndromes: April 15th, 2001
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Summary:New polymorphisms have been recently identified in CX3CRI, a corecep tor for some HIV-1 strains, one of which was associated with a strong acceleration of HIV disease progression. This effect was observed both by a case-control study in volving 63 nonprogressors (NP) from the asymptomatic long-term (ALT) cohort and Kaplan-Meier analysis of 426 French seroconverters (SEROCO cohort).These results prompted us to analyze these polymorphisms in 244 nonprogressors (NPs) and 80 rapid progressors (RPs) from the largest case-control cohort known to date, the GRIV cohort. Surprisingly, the genetic frequencies found were identical for both groups under all genetic models (p > .8). The discrepancy with the previous work stemmed only from the difference between GRIV NPs versus ALT NPs. We hypoth esized this might be due to the limited number of NPs in ALT (n = 63) and in this line we reanalyzed the data previously collected on GRIV for over 100 different genetic polymorphisms: we effectively observed that the genetic frequencies of some poly morphisms could vary by as much as 10% (absolute percentage) when computing them on the first 50 NP subjects enrolled, on the first 100, or on all the NPs tested (240 study subjects). This observation emphasizes the need for caution in case-control studies involving small numbers of subjects: p values should be low or other control groups should be used.However, the association of the CX3CR1 polymorphism with progression seems quite significant in the Kaplan-Meier analysis of the SEROCO cohort (426 individu als), and the difference observed with GRIV might be explained by a delayed effect of the polymorphism on disease. Further studies on other seroconverter cohorts are needed to confirm the reported association with disease progression.

Address correspondence and reprint requests to J-F Zagury, Labo ratoire de Physiologie Cellulaire, Université Pierre et Marie Curie, 4 place Jussieu, 75005 Paris, France;

The first two authors listed (H. Hendel and C. Winkler) made equal contributions to the work. This article does not necessarily reflect the views or policies of the U.S. Department of Health and Human Ser vices, nor does mention of trade names, commercial products, or or ganizations imply endorsement by the U.S. government.

Manuscript received September 1, 2000; accepted February 23, 2001.

© 2001 Lippincott Williams & Wilkins, Inc.